Abstract
Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.
Highlights
Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; such predicted loss-of-function variants provide insight into effector transcript and direction of biological effect
In 405,569 individuals in UK Biobank (335,660 individuals of European ancestry and 69,909 individuals of Non-European ancestry, Supplementary Table 1), we analyzed the association of 3759 predicted loss-of-function (pLOF) variants with six metabolic traits [body mass index (BMI), waist-to-hip ratio adjusted for body mass index (WHRadjBMI), height, systolic blood pressure (SBP), diastolic blood pressure (DBP), forced expiratory volume to forced vital capacity ratio (FEV1/FVC)], six cardiometabolic diseases and twelve diseases with more than 5000 cases
Beta in terms of standard deviations and reported for the effect allele pLOF predicted loss-of-function, EA effect allele, RA reference allele, AA Change amino acid change, Freq(%) Frequency(%); BMI body mass index, DBP diastolic blood pressure, SBP systolic blood pressure, WHRadjBMI waist-to-hip ratio adjusted for body mass index
Summary
Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. PLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease. We analyse pLOF variants in UK Biobank and other datasets to identify genes for which pharmacologic inhibition may protect against disease. We identify associations of pLOF variants with cardiometabolic and immune disease, prioritizing the genes GPR151, IL33, GSDMB, IFIH1, and PDE3B as potential therapeutic targets
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